Processes for preparing (r)-1-(5-chloro-[1,1`-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1`-biphenyl]-2-yl)-2,2,2-trifluoroethanone

ABSTRACT

The present invention relates to processes for the preparation of (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol, 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone, and intermediates thereof, which are useful in the preparation of inhibitors of TPH1 for the treatment of, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, low bone mass diseases, serotonin syndrome, and cancer.

FIELD OF THE INVENTION

The present invention relates to processes for the preparation of(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol,1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone, andintermediates thereof, which are useful in the synthesis of inhibitorsof TPH1 for the treatment of, for example, gastrointestinal,cardiovascular, pulmonary, inflammatory, metabolic, low bone massdiseases, serotonin syndrome, and cancer.

BACKGROUND OF THE INVENTION

Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have beenidentified. TPH1 is primarily expressed in the pineal gland andnon-neuronal tissues, such as enterochromaffin (EC) cells located in thegastrointestinal (GI) tract. TPH2 (the dominant form in the brain) isexpressed exclusively in neuronal cells, such as dorsal raphe ormyenteric plexus cells. TPH catalyzes the hydroxylation of tryptophan inthe biosynthesis of 5-HT. Thus, the pharmacological effects of 5-HT canbe modulated by agents affecting TPH.

TPH1 inhibitors are known in the art. Spirocyclic compounds disclosed inU.S. Ser. No. 14/477,948, filed Sep. 5, 2014, can inhibit TPH1 and werefound to reduce peripheral serotonin levels in animal models. Thepreparation of these compounds can include the coupling of an alcoholwith a chloro-substituted heteroaromatic compound in the presence ofbase to yield an ether intermediate that can be used to make the finalTPH1 inhibitor product. A particular chiral alcohol useful in thesynthesis of TPH1 inhibitors is(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (seeFormula A below). According to U.S. Ser. No. 14/477,948, this chiralalcohol is made by the coupling of phenyl boronic acid with(R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol. Alternativeprocesses for the preparation of the compound of Formula A are providedherein.

SUMMARY OF THE INVENTION

The present invention provides processes for preparing(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Formula A)and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (FormulaB):

as described herein.

DETAILED DESCRIPTION

The present invention provides processes for preparing(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Formula A)and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (FormulaB) as set out, for example, in Scheme I, wherein X is selected from Brand I.

In some embodiments, the invention relates to a process for preparing acompound of Formula A:

comprising, reacting a compound of Formula 1-4:

wherein X is selected from Br and I, with phenylboronic acid to producethe compound of Formula A.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some aspects of these embodiments, the reacting can be carried outunder Suzuki coupling conditions such as in the presence of a Pdcatalyst, for example, Pd₂(dppf)Cl₂. In further aspects of theseembodiments, the reacting can be carried out in the presence of asolvent comprising, for example, dioxane and/or aqueous sodiumcarbonate. In further aspects of these embodiments, to facilitate thereacting, the coupling can be carried out at elevated temperature suchas from 80 to 100° C. or at about 90° C.

In some embodiments, the compound of Formula 1-4:

wherein X is selected from Br and I,

is prepared by reducing a compound of Formula 1-3:

in the presence of a chiral catalyst.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some aspects of these embodiments, the chiral catalyst comprisesiridium such as the Ir catalyst that can be prepared by combiningdichloro(pentamethylcyclopentadienyl)iridium(III) dimer with (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine. In someaspects of these embodiments, the reduction is carried out at elevatedtemperature such as at about 30-50° C. or at about 40° C. In furtheraspects of these embodiments, the reduction is carried out in thepresence of formate as a reductant. The formate can be in the form ofsalt such as a potassium salt or sodium salt. In further aspects ofthese embodiments, the reduction is carried out in the presence of asolvent which, for example, can comprise acetonitrile.

In some embodiments, the compound of Formula 1-3:

wherein X is selected from Br and I,

is prepared by combining a compound of Formula 1-2:

with trifluoromethyltrimethylsilane (TMSCF₃).

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some aspects of these embodiments, the combining is carried out inthe presence of CsF. In further aspects of these embodiments, thecombining is carried out at a reduced temperature such as at about −10to 10° C., or at about 0° C. In further aspects of these embodiments,the combining is carried out in the presence of a solvent optionallycomprising, for example, an aromatic solvent like toluene. In furtheraspects of these embodiments, the combining further comprises the stepof adding tetra-n-butylammonium fluoride (TBAF), for example, after thecompound of Formula 1-2 is combined with TMSCF₃.

In some embodiments, the compound of Formula 1-2:

wherein X is selected from Br and I,

is prepared by coupling a compound of Formula 1-1:

with N,O-dimethylhydroxylamine hydrochloride.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some aspects of these embodiments, the coupling is carried out in thepresence of a tertiary amine such as triethylamine (TEA). In furtheraspects of these embodiments, the coupling is carried out in thepresence of a peptide coupling reagent such as(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). In further aspects of theseembodiments, the coupling is carried out using oxalyl chloride. Infurther aspects of these embodiments, the coupling is carried out in thepresence of a solvent optionally comprising, for example,dimethylformamide (DMF), or, for example, dichloromethane (CH₂Cl₂).

In some embodiments, the invention relates to a process for preparing acompound of Formula B:

wherein X is selected from Br and I,comprising reacting a compound of Formula 1-3:

with phenylboronic acid to produce the compound of Formula B;

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some aspects of these embodiments, the reacting can be carried outunder Suzuki coupling conditions such as in the presence of a Pdcatalyst, for example, Pd₂(dppf)Cl₂. In further aspects of theseembodiments, the reacting can be carried out in the presence of asolvent comprising, for example, dioxane and/or aqueous sodiumcarbonate. In further aspects of these embodiments, to facilitate thereacting, the coupling can be carried out at elevated temperature suchas from 80 to 100° C. or at about 90° C.

In some embodiments, the invention relates to a process for preparing acompound of Formula A:

comprising reducing a compound of Formula B:

in the presence of a chiral catalyst.

In some aspects of these embodiments, the chiral catalyst comprisesiridium such as the Ir catalyst that can be prepared by combiningdichloro(pentamethylcyclopentadienyl)iridium(III) dimer with (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine. In furtheraspects of these embodiments, the reduction is carried out at elevatedtemperature such as at about 30-50° C. or at about 40° C. In furtheraspects of these embodiments, the reduction is carried out in thepresence of formate as a reductant. The formate can be in the form ofsalt such as a potassium salt or sodium salt. In further aspects ofthese embodiments, the reduction is carried out in the presence of asolvent which, for example, can comprise acetonitrile.

In some embodiments, the present invention is directed to a compound ofFormula A prepared by a process described herein.

In some embodiments, the invention is directed to a compound of FormulaB:

In some embodiments, the invention is directed to a compound of FormulaB prepared by a process described herein.

In some embodiments, the invention is directed toward a compound ofFormula 1-4:

wherein X is selected from Br and I.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some embodiments, the invention is directed to a compound of Formula1-4 prepared by a process described herein.

In some embodiments, the invention is directed toward a compound ofFormula 1-3:

wherein X is selected from Br and I.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some embodiments, the invention is directed to a compound of Formula1-3 prepared by a process described herein.

In some embodiments, the invention is directed toward a compound ofFormula 1-2:

wherein X is selected from Br and I.

In some aspects of these embodiments, X is I. In other aspects of theseembodiments, X is Br.

In some embodiments, the invention is directed to a compound of Formula1-2 prepared by a process described herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination. While certain of the processes steps areillustrated in Scheme I above, it is intended that the individualprocess steps may be claimed individually or in any combination. It isnot intended that the processes be limited to an overall process havingeach and every step depicted in Scheme I.

The term “compound,” as used herein, is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified. Compounds herein identified by name orstructure without specifying the particular configuration of astereocenter are meant to encompass all the possible configurations atthe stereocenter. For example, if a particular stereocenter in acompound of the invention could be R or S, but the name or structure ofthe compound does not designate which it is, than the stereocenter canbe either R or S.

The term “compound,” as used herein, is further meant to include allisotopes of atoms occurring in the structures depicted. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds disclosed herein are substantiallyisolated. By “substantially isolated” is meant that the compound is atleast partially or substantially separated from the environment in whichit was formed or detected. Partial separation can include, for example,a composition enriched in the compounds of the invention. Substantialseparation can include compositions containing at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about 97%, or at least about 99% byweight of the compounds of the invention, or salt thereof.

As used herein, the phrase “elevated temperature” refers to atemperature higher than about room temperature (20-26° C.).

As used herein, the phrase “reduced temperature” refers to a temperaturelower than about room temperature.

As used herein, the phrase “Suzuki coupling conditions” refers toreaction conditions that result in the formation of a carbon-carbon bondbetween aromatic moieties, one of which includes a halogen substituentand the other which includes a boronic acid or boronate substituent,where the reaction is carried out in the presence of a Pd(0) catalyst.

As used herein, the phrase “chiral catalyst” is a substance that pushesa reaction to favor one stereoisomer over another. In some embodiments,the chiral catalyst is a chiral coordination complex, such as a chiralcoordination complex of iridium.

The present application also includes salts of the compounds describedherein. In some embodiments, the salts are pharmaceutically acceptablesalts which are conventional non-toxic salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety. The phrase “pharmaceuticallyacceptable” is employed herein to refer to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry; or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography. The compounds obtained by the reactions can be purifiedby any suitable method known in the art. For example, chromatography(medium pressure) on a suitable adsorbent (e.g., silica gel, alumina andthe like), HPLC, or preparative thin layer chromatography; distillation;sublimation, trituration, or recrystallization. The purity of thecompounds, in general, are determined by physical methods such asmeasuring the melting point (in case of a solid), obtaining a NMRspectrum, or performing a HPLC separation. If the melting pointdecreases, if unwanted signals in the NMR spectrum are decreased, or ifextraneous peaks in an HPLC trace are removed, the compound can be saidto have been purified. In some embodiments, the compounds aresubstantially purified.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Wuts and Greene, Greene's Protective Groups inOrganic Synthesis, 4^(th) Ed., John Wiley & Sons: New York, 2006, whichis incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the reaction step, suitable solvent(s) for that particularreaction step can be selected. Example solvents include water, alkanes(such as pentanes, hexanes, heptanes, cyclohexane, etc., or a mixturethereof), aromatic solvents (such as benzene, toluene, xylene, etc.),alcohols (such as methanol, ethanol, isopropanol, etc.), ethers (such asdialkylethers, methyl tent-butyl ether (MTBE), tetrahydrofuran (THF),dioxane, etc.), esters (such as ethyl acetate, butyl acetate, etc.),halogenated hydrocarbon solvents (such as dichloromethane (DCM),chloroform, dichloroethane, tetrachloroethane), dimethylformamide (DMF),dimethylsulfoxide (DMSO), acetone, acetonitrile (ACN),hexamethylphosphoramide (HMPA) and N-methyl pyrrolidone (NMP). Suchsolvents can be used in either their wet or anhydrous forms.

EXAMPLES

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

¹H NMR Spectra were acquired on a Varian Mercury Plus 400 MHzspectrometer. For typical ¹H NMR spectra, the pulse angle was 45degrees, 8 scans were summed and the spectral width was 16 ppm (−2 ppmto 14 ppm). Typically, a total of about 32768 complex points werecollected during the 5.1 second acquisition time, and the recycle delaywas set to 1 second. Spectra were collected at 25° C. ¹H NMR Spectrawere typically processed with 0.3 Hz line broadening and zero-filling toabout 131072 points prior to Fourier transformation. Chemical shiftswere expressed in ppm relative to tetramethylsilane. The followingabbreviations are used herein: br=broad signal, s=singlet, d=doublet,dd=double doublet, ddd=double double doublet, dt=double triplet,t=triplet, td=triple doublet, tt=triple triplet q=quartet, m=multiplet.

Liquid chromatography—mass spectrometry (LCMS) experiments to determineretention times and associated mass ions were performed using an AgilentZorbax Bonus RP (reverse phase) column, 2.1×50 mm, 3.5 μm particle size,at a temperature of 50° C. and at a flow rate of 0.8 mL/min, 2 μLinjection, mobile phase: (A) water with 0.1% formic acid and 1%acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retentiontime given in minutes. Method details: (I) ran on a Binary PumpG1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 massspectrometer in positive and negative ion electrospray mode withUV-detection at 220 and 254 nm with a gradient of 50-95% (B) in a 2.5min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).

Example 1 Preparation of(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Formula A)

The compound of Formula A was prepared as described below (see alsoScheme I above) using synthetic intermediates 1-1, 1-2, 1-3, and 1-4.

Step 1: 4-chloro-2-iodo-N-methoxy-N-methylbenzamide (1-2, X=I)

To a solution of 4-chloro-2-iodobenzoic acid (1-1, X=I)(CAS#:13421-13-1; Aldrich, SKU: 560146) (3 g, 10.62 mmol) andN,O-dimethylhydroxylamine hydrochloride (CAS#: 6638-79-5; Sigma Aldrich,SKU: D163708) (1.2 g, 12.31 mmol) in dimethylformamide (DMF) (30 mL),was added dropwise triethyl amine (TEA) (7.4 mL, 53.14 mmol), followedby the addition of(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU) (6.1 g, 16.05 mmol). The reactionmixture was stirred at RT for 16 h and then diluted with CH₂Cl₂ and H20,and the aqueous layer was extracted with CH₂Cl₂ (4×20 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered,concentrated in vacuo and purified by silica gel chromatography (ethylacetate/hexanes 1:4) to afford the title compound as a white solid (3.2g. LCMS (MH+): 325.9. ¹H NMR (400 MHz, CDCl₃-d): δ3.11-3.38 (m, 3H),3.47-3.90 (m, 3H), 7.20 (d, J=8 Hz,1H), 7.37 (d, J=2 Hz, 1H), 7.84(s,1H).

Step 2: 1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanone (1-3, X=I)

To a solution of 4-chloro-2-iodo-N-methoxy-N-methylbenzamide (1-2, X =I)(Prepared in Step 1: 1.9 g, 5.84 mmol) and CsF (222 mg, 1.46 mmol) intoluene (5 mL), was added dropwise trifluoromethyltrimethylsilane(TMSCF3) (2.2 mL, 14.88 mmol) at 0° C. The reaction mixture was thenwarmed to RT and stirred at that temperature for 20 h. Then, water (6mL) and tetra-n-butylammonium fluoride (TBAF) (6 mL, 1 M in THF) wereadded to the reaction mixture, and the reaction mixture was heated to50° C. for 2 h. The reaction mixture was then cooled to RT and extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, concentrated in vacuo andpurified by silica gel chromatography (100% hexanes) to provide thetitle compound as a yellow oil (1.39 g). LCMS (MH+): 334.9. ¹H NMR (400MHz, CDCl₃-d): δ7.51 (dd, J=10, 6 Hz,1H), 7.37 (dd, J=10, 7 Hz, 1H),7.84 (d, J=2 Hz,1H).

Step 3: (R)-1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanol (1-4)

To a solution of 1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanone (1-3,X=I) (Prepared in Step 2; 4.0 g, 11.9 mmol) in CH₃CN (20 mL) was addedchiral iridium catalyst (20 mL of a 0.1 mM aqueous solution, prepared bymixing dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (CAS#:12354-84-6, 4.0 mg, 0.005 mmol) and (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (CAS#144222-34-4, Strem Chemicals catalogue #07-2371, 3.6 mg, 0.009 mmol) inwater (40 mL) and heating the resultant mixture to 40° C. for 3 h). Thereaction mixture was then charged with potassium formate (HCOOK) (5.03g, 59.80 mmol), and heated at 40° C. for 12 h. Then the reaction mixturewas cooled to RT and diluted with ethyl acetate and saturated aqueoussolution of NaCl. Layers were separated and the aqueous layer wasextracted with ethyl acetate (4×30 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to afford the title compound as a yellow solid (4.1 g, crude) thatwas used in the following steps without further purification. LCMS(MH+): 336.9. ¹H NMR (400 MHz, CDCl₃-d): δ3.5 (bs, 1H), 5.10 (dd, J=10Hz, 6 Hz, 1H), 7.29 (dd, J=10, 6 Hz,1H), 7.45 (dd, J=10, 7 Hz,1H),7.71(d, J=2 Hz,1H).

Confirmation of the (R) configuration was confirmed by Mosher Esteranalysis. To a solution of(R)-1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanol (50 mg, 0.15 mmol)in tetrahydrofuran (THF) (1 mL, anhydrous) was added4-dimethylaminopyridine (23 mg, 0.19 mmol) and(R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (36 μL, 0.19mmol). The resulting mixture was stirred at room temperature for 1 hthen filtered. The filtrate was concentrated and purified by preparativethin layer chromatography (TLC) (ethyl actate:hexanes/1:40) to afford(R)-(R)-1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethyl3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (50 mg, 0.09 mmol, 98% e.e.which was confirmed by ¹H NMR).

Step 4: (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol(Formula A)

A solution of (R)-1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanol (1-4)(3.1 g, 9.21 mmol), phenylboronic acid (CAS#: 98-80-6; Sigma Aldrich,SKU P20009) (1.2 g, 10.2 mmol), and Pd(dppf)Cl₂ (CAS#72287-26-4; SigmaAldrich SKU: 697230) (337 mg, 0.46 mmol) in dioxane (30.0 mL) and Na₂CO₃(10.0 mL, 2.0 M aqueous solution) was purged with Na three times, andthe resultant reaction mixture was heated to 90° C. for 2 h. Thereaction mixture was then cooled to RT and diluted with CH₂Cl₂ andwater. Layers were separated and the aqueous layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and purified by silica gel chromatography(ethyl actate/hexanes 1/10) to afford the title compound as a whitesolid (2.4 g over 2 steps). ¹H NMR (400 MHz, CDCl₃-d): δ3.51 (m, 1H),5.08-5.13 (q, J=20, 7 Hz,1H),7.26-7.30 (m,4H), 7.42-7.46 (m, 3H), 7.70(d,J=8 Hz,1H). The (R) configuration of the title product was confirmedby Mosher Ester analysis (98% e.e.) as described above for the productof Step 1: (R)-1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanol.

Example 2 Preparation of1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (Formula B)

The compound of Formula B was prepared as described below (see alsoScheme I above) using synthetic intermediates 1-1, 1-2, and 1-3.

Step 1: 4-chloro-2-iodo-N-methoxy-N-methylbenzamide (1-2, X=I)

To a solution of 4-chloro-2-iodobenzoic acid (1-1, X=I) (296 g, 1.1 mol)in CH₂Cl₂ (3 L) and DMF (2 mL) was added oxalyl dichloride (266.1 g, 2.1mol) dropwise at 0° C. over a period of 1 h. The resultant reactionmixture was stirred at 0° C. for 2 h and then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ and concentrated twice. Then the residuewas dissolved in CH₂Cl₂ (1 L) and cooled to 0° C., followed by thedropwise addition of a mixture of N,O-dimethylhydroxylaminehydrochloride (Sigma Aldrich, SKU: D163708; 112.4 g, 1.15 mol) in CH₂Cl₂(1 L) and triethyl amine (1 L, 3.15 mol) at 0° C. over a period of 1 h.The reaction mixture was then warmed to RT and stirred at thattemperature for 16 h. After this time, the mixture was diluted with H₂Oand the aqueous layer was extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, concentratedin vacuo and purified by silica gel chromatography (ethylacetate/hexanes 1/4) to afford the title compound (320 g) as a whitesolid LCMS (MH+): 325.9. ¹H NMR (400 MHz, CDCl₃-d): δ3.11-3.38 (m, 3H),3.47-3.90 (m, 3H), 7.20 (d, J=8 Hz, 1H), 7.37 (d, J=2 Hz, 1H), 7.84 (s,1H).

Step 2: 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone(Formula B)

A solution of 1-(4-chloro-2-iodophenyl)-2,2,2-trifluoroethanone (1-3,X=I, prepared in Example 1, Step 2) (145 g, 0.43 mol), phenylboronicacid (CAS#: 98-80-6; Sigma Aldrich, SKU P20009; 55.5 g, 0.455 mol) andPd(dppf)C12 (CAS#72287-26-4; Sigma Aldrich SKU: 697230; 9.5 g, 0.013mol) in dioxane (1450 mL) and Na₂CO₃ (435 mL, 2.0 M aqueous solution)was purged with Na and stirred at 90° C. for 2 h. After this time, thereaction mixture was cooled to RT and then diluted with H₂O. Layers wereseparated and the aqueous layer was extracted with ethyl acetate and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated in vacuo and purified by silica gelchromatography (100% hexanes) to afford the title compound (115 g) as awhite solid. LCMS (MH+): 284.66. ¹H NMR (400 MHz, CDCl₃-d): δ7.23-7.27(m, 2H), 7.42-7.44 (m, 3H), 7.47-7.49 (m, 2H), 7.67-7.70 (m,1H)

Example 3 Preparation of(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Formula A)

The compound of Formula A was prepared as described below (see alsoScheme I above) using the compound of Formula B as synthetic startingmaterial.

To a 22 L 3-necked reactor, fitted with a mechanical stirrer, atemperature probe, and a N₂ inlet, were charged sequentiallydichloro(pentamethyl cyclopentadienyl)iridium (III) dimer ([Cp*IrCl2]2,1.52 g, 1.90 mmol, CAS: 12354-84-6),(1R,2R)-(−)-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (1.52 g,4.15 mmol, CAS: 144222-34-4, Strem Chemicals catalogue #07-2371) andwater (8 L) at RT. The resulting reaction mixture was heated to 40° C.for 3 h to provide a homogeneous orange solution. To this activecatalyst solution at the current temperature (40° C.), was addedpotassium formate (1476 g, 17.55 mol), and a solution of1-(2-phenyl-4-chlorophenyl)-2,2,2-trifluoroethanone (compound of FormulaB prepared in Example 2) (1000 g, 3.51 mol) in CH₃CN (8 L). The reactionmixture was then stirred at 40° C. for 2 h and then cooled to RT and thelayers were separated. The aqueous layer was extracted with MTBE (2×3 L)and the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide(R)-1-(2-phenyl-4-chlorophenyl)-2,2,2-trifluoroethanol (1006 g) as athick yellow oil used without further purification.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1-81. (canceled)
 82. A compound which is a compound of Formula B:


83. A compound which is a compound of Formula 1-3:

wherein X is I.